Is DROSHA p.Arg234Ter (c.700C>T) pathogenic?

DROSHA p.Arg234Ter (c.700C>T) is classified Uncertain significance in DROSHA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-21). Very rare (popmax 0.00017%, nfe); Associated with MicroRNA processor tumor predisposition syndrome.

What condition is associated with DROSHA p.Arg234Ter (c.700C>T)?

DROSHA p.Arg234Ter (c.700C>T) is associated with MicroRNA processor tumor predisposition syndrome (ClinVar).

How common is DROSHA p.Arg234Ter (c.700C>T) in the general population?

DROSHA p.Arg234Ter (c.700C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

DROSHA p.Arg234Ter

c.700C>T · VCV3356474

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

MicroRNA processor tumor predisposition syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 5 of 36
REVEL	0.222	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.4, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,862 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,708 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DROSHA
Protein: p.Arg234Ter
Coding: c.700C>T
MANE Select: NM_001382508
Type: single nucleotide variant
Location: chr5:31526233 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.94 · 12 PDB
Residue 234: the 'disordered' region

Full DROSHA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MicroRNA processor tumor predisposition syndrome

Similar variants

DROSHA p.Asp248His Uncertain significance ★★ ⚠ same condition
DROSHA p.Pro100Leu Uncertain significance ★★ ⚠ same condition
DROSHA p.Arg287Ter Uncertain significance ★ same condition
DROSHA p.Arg354Cys Uncertain significance ★ ⚠ same condition
DROSHA p.Arg40Thr Uncertain significance ★ ⚠ same condition
DROSHA p.Asp1219Gly Uncertain significance ★ ⚠ same condition
DROSHA p.Pro211Thr Uncertain significance ★ ⚠ same condition
DROSHA p.Trp523Ter Uncertain significance ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/drosha-p-arg234ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown